This is a renewal application for this Program Project Grant under ARRA funding. This Program Project combines the expertise of two institutions, The University of Vermont (UVM) and the nearby Trudeau Institute. The UVM investigators have expertise is cell signaling, immunogenetics, and viral immunology, whereas the Trudeau investigators have strength in immune memory and in vivo infectious models. The renewal application represents an effort to translate our previous studies in vitro to in vivo infectious diseases. The central theme is the process by which infectious agents engage the innate immune system to influence the generation and fate of effector CD4 T cells. Of particular interest is the interface between innate and adaptive immune responses. Project 1 (Dr. Cory Teuscher) studies newly discovered roles for histamine (produced by the innate immune system) in activation and differentiation of CD4 T cells during infection with Coxsackievirus and implications in the development of virus-induced myocarditis. Project 2 (Dr. Ralph Budd) examines [unreadable][unreadable] T cells in humans and mice in response to infection (B. burgdorferi and Coxsackievirus) their ability to recognize non-polymorphic CD1 molecules, which are upregulated following interactions of infectious organisms. In turn, the [unreadable][unreadable] T cells activate dendritic cells to produce cytokines and costimulatory molecules that are important to the activation of na[unreadable]ve CD4 T cells. Project 3 (Dr. Mercedes Rincon) examines the role of IL-6 (produced by innate immune cells) in enhancing antibody response against influenza virus by inducing IL-21 production by CD4 T cells. An additional project (original Project 4) directed by Dr. Susan Swain, funded as a separate R01, integrates aspects of the other projects to study the effect of inflammatory cytokines (e.g. IL-6, TNFa) on the survival of CD4 effector cells generated during influenza virus infection and the impact on virus specific memory T cells. Significance: The interface between the innate and adaptive immune response is poorly understood the findings will likely be highly valuable in the future design of optimal vaccines. SREigLEnVifAicNaCnEc(eSe:eTinhsetruicntitoenrsf)a: ce between the innate and adaptive immune response is poorly understood the fSinigdninifgicsawncilel l:ikTehlye binetehrifgahcleybveatluwaebelne tinhethinenfauteuraendeasdiganptoivfeopimtimaulnveacrecsinpeosn.se is poorly understood;the findings will likely be highly valuable in the future design of optimal vaccines. PROJECT/PERFORMANCE SITE(S) (if additional space is needed, use Project/Performance Site Format Page) Project/Performance Site Primary Location Organizational Name: University of Vermont and State Agricultural College DUNS: 06-681-1191 Street 1: D305 Given Building Street 2: 89 Beaumont Avenue City: Burlington County: Chittenden State: VT Province: Country: USA Zip/Postal Code: 05405-0068 Project/Performance Site Congressional Districts: Vermont-at-large Additional Project/Performance Site Location Organizational Name: Trudeau Institute DUNS: 020658969 Street 1: 154 Algonquin Avenue Street 2: City: Saranac Lake County: Franklin State: NY Province: Country: USA Zip/Postal Code: 12983 Project/Performance Site Congressional Districts: NY-24 PHS 398 (Rev. 11/07) Page Form Page 2